tbuckley/cabot-search huggingface dataset:
Dysregulation of the endomembrane homeostasis triggers vascular smooth muscle cell phenotype switching
Authors: N Hense, B Mir, N Marx, C Goettsch
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft Background Cardiovascular diseases are a leading cause of mortality globally, with cardiovascular calcification as a prominent predictor and contributor. Notably, microcalcifications might cause atherosclerotic plaque rupture, leading to myocardial infarction. Calcified plaque remodeling accompanies phenotypic modulation of vascular smooth muscle cells (SMCs). Previously, we showed that extracellular vesicles (EVs) released from calcifying SMCs are pivotal for microcalcification formation. EVs originate from the endolysosomal system. The lipid kinase FYVE-type zinc finger containing phosphoinositide kinase (PIKfyve) plays a role in the endolysosomal maturation. Here, we investigated how modulation of the endolysosomal system intersects with SMC phenotype regulation. Methods and Results In calcified arteries and SMCs, we observed increased PIKfyve expression. Inhibition of PIKfyve with the small molecule Apilimod inhibited osteogenic differentiation of SMCs in an in vitro calcification model. Apilimod reduced tissue non-specific alkaline phosphatase (TNAP) – an early marker of SMC calcification on mRNA (-79%, p&amp;lt;0.01), protein (-96%, p&amp;lt;0.01) and activity (-92%, p&amp;lt;0.01) levels. Additionally, matrix mineralization and collagen network formation are inhibited. SMC-secreted EVs exhibited a lower mineral content and reduced aggregation potential assessed by osteosense-based flow cytometry and turbidity assays. Transcriptome analyses revealed that the anti-calcifying effect is accompanied by a decreased expression of contractile SMC genes. Validation by RT-PCR supported that SMC-specific markers (ACTA2, SM22) and the key SMC transcription factor MYOCD were downregulated, while the expression of macrophage-like SMC markers (LGALS3, CD68) was induced. On the other hand, Apilimod increased the expression of adipogenic transcription factors (CEBPA, PPARG) and genes of the cholesterol and fatty acid metabolism pathways (SREBF2, HMGCR, FABP3, CD36) and induced the nuclear translocation of PPARγ, the main regulator of adipogenic differentiation. Fluorescence-based assays revealed increased fatty acid and disrupted low-density lipoprotein (LDL) uptake in Apilimod-treated SMCs. In Ldlr-deficient mice fed a high-fat, high-cholesterol diet for 15 weeks and treated with Apilimod for 5 weeks, we found differentially distributed plaque lipid depositions detected by Oil Red O staining. Conclusion Disrupting the endolysosomal maturation by PIKfyve inhibition ameliorates SMC calcification and induces a phenotypic adipogenic-like, pro-inflammatory adaption. Our data elucidates the importance of SMC phenotype monitoring during therapeutic interference. The exact lineage characteristics of these SMCs remain to be further investigated.
Predicting patient-reported symptom clusters in prostate cancer patients: A machine learning approach
Authors: E. Rammant, E. Deman, L. Poppe, R. Bultijnck, P. Dirix, G. De Meerleer, K. Haustermans, A. Van Hecke, D. Azria, J. Chang-Claude, A. Choudhury, D. De Ruysscher, M. Lambrecht, B.S. Rosenstein, P. Seibold, E. Sperk, R.P. Symonds, R. Valdagni, A. Vega, A. Webb, C. West, L. Veldeman, V. Fonteyne, S. Van Hoecke
Journal: European Urology (2022)
Palliative care integration and end-of-life outcomes in veterans with metastatic colon cancer.
Authors: Ye Aung, Vidit Kapoor, Paromita Datta
Journal: Journal of Clinical Oncology (2022)

e24069 Background: Metastatic Colon Cancer is associated with an overall poor prognosis with an estimated 5 year survival rate &lt; 14% according to SEER data. There has been a movement in national society guidelines to advocate for increased utilization and integration of palliative care for all patients with metastatic solid tumors. Here through retrospective chart review we examined the impact of palliative care consultation on end of life outcomes at the Audie L Murphy Veterans Affairs Medical Center in San Antonio. Methods: With the help of the VA tumor registry we compiled a list of 103 Veterans diagnosed with metastatic colon cancer and who were seen from January 2013-December 2021 at the Audie L Murphy VAMC. Data was abstracted from electronic chart review in CPRS and analyzed to compare differences in end of life outcomes between patients that received palliative care and those that did not. Statistical significance was calculated using Fisher's Exact Test. Results: Overall 53/79 (67%) of Veterans were seen by a palliative care physician prior to death which is higher than the national average 45%. There was an overall high rate of completion of advance directives in this clinic 82/103 (79.6%), however, patients who were seen by palliative care were more likely to have completed advance directives (90.8% vs 60.5%, p &lt; .001). Patients seen by palliative care were also more likely to have their setting of death occur outside of the hospital (86.4% vs 64%, p &lt; .04), they were also less likely to be admitted to the ICU &lt; 30 days prior to death (9.8% vs 30.4%, p &lt; .04) and they were less likely to receive CPR &lt; 30 days prior to death (3.9% vs 22.3%, p &lt; .03). We did not find any statistically significant differences in hospice enrollment rates, (79.2% vs 56% p &lt; .057) nor did we find any differences in chemotherapy &lt; 30 days prior to death (15.4% vs 19.2% p &lt; .75). Our study was limited by the smaller sample size of patients not receiving palliative care. Of note our population was overwhelmingly male (97%) and the average age at diagnosis of metastatic disease was 65.6. Conclusions: Overall the utilization of palliative care in Veterans with metastatic colon cancer is associated with better advanced care planning and decreased aggressiveness in end of life care. These results are consistent with other studies and our retrospective analysis provides more data supporting the increased utilization of Palliative Care for Veterans with metastatic colon cancer.
EPEN-21. Developing a sensitive method for detection of minimal residual disease in ependymoma using metabolomic analysis of cerebrospinal fluid
Authors: Alison Woodward, Laudina Amugi, Kishan Patel, Charlotte Kilpatrick, Dong-hyun Kim, Madhumita Dandapani
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Ependymoma (EPN) is the second most common malignant paediatric brain tumour with poor survival and significant neuro-cognitive impairment from current treatments (surgery and radiotherapy). Relapse occurs in 50% of patients within 2 years, despite no evidence of tumour on MRI. This suggests that they have minimal residual disease (MRD) at the end of treatment. Developing an accurate MRD detection method could help select patients who would benefit from further continuation chemotherapy, thereby improving survival. There is also an unmet need for an accurate test to diagnose relapse early when the disease could be more treatable. METHODS: Pilot untargeted liquid chromatography-mass spectrometry (LC-MS) analysis was carried out in cerebrospinal fluid (CSF) samples from patients with ependymoma. CSF from patients in remission from leukemia were used as controls. RESULTS: Pilot data from analysis of CSF using LC-MS demonstrates that this is a feasible approach to characterise CSF metabolomic profile. Also, EPN CSF profile is significantly different from control CSF, with significant elevation of few key metabolites (Vitamin D derivatives and betaine) in EPN CSF compared to control CSF. Immunohistochemical analysis of EPN tumour tissue microarrays confirms the expression of betaine / one-carbon pathway enzymes such as methionine synthase and betaine—homocysteine S-methyltransferase. Further validation of CSF profile with tumour metabolomic profile and serial CSF sample profiling is currently underway. Subgroup-specific differences and targeted analysis to develop a panel of biomarkers is also being explored. CONCLUSION: Early results suggest that CSF-based metabolite profiling using LC-MS is feasible and could help detect minimal residual disease in ependymoma. Further validation is required to analyse subgroup-specific differences and correlate quantitative changes in metabolites with changing disease burden.
An mTOR siRNA‐Loaded Spermidine/DNA Tetrahedron Nanoplatform with a Synergistic Anti‐Inflammatory Effect on Acute Lung Injury (Adv. Healthcare Mater. 11/2022)
Authors: Chaowang Huang, Qianyi You, Jing Xu, Di Wu, Huaping Chen, Yuhang Guo, Jiancheng Xu, Mingdong Hu, Hang Qian
Journal: Advanced Healthcare Materials (2022)

Anti-Inflammatory Therapy In article number 2200008 by Mingdong Hu, Hang Qian, and co-workers, a dual therapy DNA nanoplatform consisting of spermidine and mTOR siRNA is constructed and a synergistic anti-inflammatory effect is demonstrated in vitro and in an acute lung injury mouse model.
Role of dorsal vascular complex preservation in robot-assisted radical prostatectomy
Authors: G. Gaudio, G. Cochetti, G. Felici, G. Maiolino, A. Tancredi, G. Manfredini, F. Pastore, R. La Mura, A. Vitale, M. Russo, E. Mearini
Journal: European Urology (2022)
Genetic Architecture of Azoospermia—Time to Advance the Standard of Care
Authors: Margot J. Wyrwoll, Nils Köckerling, Matthias Vockel, Ann-Kristin Dicke, Nadja Rotte, Eva Pohl, Jana Emich, Marius Wöste, Christian Ruckert, Rebecca Wabschke, Jochen Seggewiss, Susanne Ledig, Ann-Christin Tewes, Yvonne Stratis, Jann F. Cremers, Joachim Wistuba, Claudia Krallmann, Sabine Kliesch, Albrecht Röpke, Birgit Stallmeyer, Corinna Friedrich, Frank Tüttelmann
Journal: European Urology (2022)
A phase 1/2 trial of lurbinectedin (L) in combination with pembrolizumab (P) in relapsed small cell lung cancer (SCLC): The LUPER study.
Authors: Antonio Calles, Alejandro Navarro, Bernard Doger, Maria J. de Miguel, Rosa Maria Alvarez Alvarez, Victor Moreno, Jorge Ramón, María del Mar Galera López, Tatiana Hernandez-Guerrero, Elena Corral, Emiliano Calvo
Journal: Journal of Clinical Oncology (2022)

8581 Background: L is a novel anticancer agent that inhibits trans-activated transcription and modulates the tumor microenvironment. L is approved by the FDA for metastatic SCLC patients (pts) with progressive disease (PD) on or after platinum-based chemotherapy (CT). The LUPER study is assessing the safety, tolerability, and preliminary efficacy of L+P as second-line regimen for SCLC pts after failure of platinum-based CT. Phase 1 data are presented here. Methods: In this phase 1/2 trial (NCT04358237), adult pts with histologically confirmed SCLC, PD to a previous CT-containing regimen (≥4 weeks before study initiation), no prior exposure to immunotherapy, ECOG PS of 0-1, and measurable disease as per RECIST 1.1 are eligible. Pts with treated, stable, and asymptomatic brain metastases (BMs) are allowed. A 3+3 dose-escalation was done to determine the recommended phase 2 dose (RP2D) of L+P. L was dosed at 2.4 mg/m 2 and 3.2 mg/m 2 IV Q3W in the dose level (DL)1 and 2, respectively, in combination with fixed dose of P (200 mg IV Q3W). The RP2D was the highest DL at which 0/3 pts or ≤1/6 pts experienced dose-limiting toxicities (DLTs) during the first cycle. Treatment was administered until PD, unacceptable toxicity, or consent withdrawal. Secondary endpoints include safety as per CTCAE 5.0, preliminary efficacy, and pharmacokinetics. Results: Thirteen pts were enrolled across 3 hospitals in Spain (DL1, n = 7; DL2, n = 6). Median age was 66 (range 43–78) years, 46.2% were female, 61.5% had ECOG PS of 1, 38.5% had platinum-free interval &lt; 90 days, 30.8% had LDH &gt; upper normal limit, and 15.4% had BMs. One DLT (G3 asthenia) and one G4 neutropenia lasting &gt; 3 days (controlled with G-CSF prophylaxis upon C2, without requiring dose delay or modification) occurred in the DL1. No DLT were reported in the DL2. The RP2D was identified as 3.2 mg/m 2 L and 200 mg P IV Q3W. At data cutoff (Jan 21, 2022), 5 (38.4%) pts remained on treatment (1 pt in DL1 discontinued due to COVID-19 in cycle 1). Median duration of treatment was 2.1 (0–11.8) months, 5 (38.5%) pts had ≥8 cycles, and median relative dose intensity of L and P were 91.1% and 95.7%, respectively. Immune-related AEs (G2 pneumonitis; G3 ALT increased) led to P discontinuation in 2 (15.4%) pts. Responses were shown in both DLs, with ORR of 30.8% (1 confirmed complete response and 3 partial responses); 3 pts had stable disease (SD; including 1 patient with SD &gt; 12 weeks) and 5 (38.5%) pts experienced PD. Conclusions: This is the first report to demonstrate a manageable safety profile and preliminary efficacy of second-line L+P for relapsed SCLC pts. This combination warrants further confirmation in the ongoing expansion phase 2. Clinical trial information: NCT04358237.
Complete minimally-invasive surgery is feasible for Renal Cancer with level IV intracardiac tumour thrombus
Authors: P. Dell'Oglio, M. Longoni, S. Tappero, S. Secco, E. Palagonia, O. Alberto, F. Mulazzani, O. Amici, A. Brunetti, A.M. Bocciardi, A. Galfano
Journal: European Urology (2022)
Development of PLM-102, a novel dual inhibitor of FLT3 and RET as a new therapeutic option for acute myeloid leukemia.
Authors: Myungjin Kim, Su-jin Oh, WooChan Kim, Yong June Choi, Jae-Seon Lee, So-Deok Lee, Jin-Hee Park, Eun Ji Lee, Keon Wook Kang, Soo Yeon Jang, Yong-Chul Kim
Journal: Journal of Clinical Oncology (2022)

e15103 Background: Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all acute myeloid leukemia (AML) cases, with the internal tandem duplication (ITD) representing the most common type of FLT3 mutation (FLT3-ITD; approximately 25% of all AML cases). Although several FLT3 inhibitors have been developed, occurrence of secondary TKD mutations of FLT3 such as FLT3/D835Y and FLT3/F691L causes the acquired resistance to the current FLT3 inhibitors and eventually become a key area of unmet medical needs. Here, we have revealed that PLM-102, a novel, orally active FLT3 and RET dual inhibitor, has a potential to overcome the acquired resistance to current FLT3 inhibitors. Methods: 1. Kinase assay- Biochemical assays for FLT3 (WT and D835Y) and RET (WT and Mutants) were performed according to ADP-Glo kinase assay protocol(Promega). 2. Cell proliferation and Apoptosis- Human leukemia cell line MV4-11 and MOLM-14 were purchased from ATCC and DSMZ. Cells were seeded at a density of 2 X 10 3 cells per well and treated with the indicated concentrations of inhibitors for 72 hours at 37°C. Cell viability was determined by an Alamar Blue assay (Bio-Rad). Caspase-3/7 activity was measured by using the Caspase-Glo 3/7 assay (Promega). 3. Western blot analysis- Immunoblotting using MOLM-14 cells was performed using anti-phospho-FLT3 (Cell Signaling Technology #3461) and anti-FLT3 antibody (Cell Signaling Technology #3462). 4. In vivo mouse models- The MV4-11 and MOLM-14 cells are implanted into the subcutaneous space of the left flank of the mice. Resulting tumors are monitored by calipering twice weekly. Treatment started after randomization when tumor volumes had reached a size of approximately 100-150 mm 3 . For statistical analysis, analysis of variance (ANOVA) was performed using Prism 9.0 to examine statistical differences. Results: In compared to FDA-approved Gilteritinib, PLM-102 showed stronger sub-nanomolar IC 50 values in FLT3 kinases regardless of wild-type, ITD, TKD and ITD/TKD mutants in both kinase- and cell-based assays. PLM-102 inhibited phosphorylation of FLT3 and its downstream signaling pathways, and induced apoptosis as evidenced by PARP-cleavage and caspase-3 activation. Moreover, PLM-102 showed an excellent anti-tumor activity in mouse xenograft models implanted with MV4-11 and MOLM-14 AML cells. Conclusions: Taken together, PLM-102 showing potent anti-cancer activity against various in vitro and in vivo AML models could be developed as a valuable agent overcoming the acquired resistance to the current FLT3 inhibitor.
Targeting genomic instability in extrapulmonary small cell neuroendocrine cancers: A phase II study with ATR inhibitor berzosertib and topotecan.
Authors: Nobuyuki Takahashi, Parth Anil Desai, Linda Sciuto, Samantha Nichols, Seth M. Steinberg, Anish Thomas
Journal: Journal of Clinical Oncology (2022)

8518 Background: Extra-pulmonary small cell neuroendocrine cancers (EP-SCNC) are rare cancers with no standard treatments at relapse that share molecular similarities with small cell lung cancer (SCLC). Concurrent inhibition of ataxia telangiectasia and Rad3 related (ATR) and topoisomerase 1, key enzymes for maintaining genomic stability, exacerbated replication stress in SCLC cells and produced durable antitumor responses in patients with relapsed SCLC (Cancer Cell 2021; PMID: 33848478). Methods: Combination of berzosertib and topotecan was evaluated in patients with relapsed EP-SCNC (NCT02487095). Berzosertib was administered at 210 mg/m 2 on days 2 and 5 and topotecan 1.25 mg/m 2 on days 1-5 in 21-day cycles. Whole exome sequencing (WES) and transcriptome analyses were performed to assess the genomic features associated with response. Results: Fifteen patients with EP-SCNC involving various primary sites were enrolled [three each: cervix, transformed SCLC; two each: bladder, breast, prostate; one each: gallbladder, ovary, rectum]. Two patients (13.3%: breast and rectum) achieved a confirmed partial response (PR; -72.2% and -48.5% tumor reduction in size) lasting 6.9 and 5.8 months. Responses occurred irrespective of platinum-sensitivity or prior treatment with topotecan or immunotherapy. Pre-treatment tumor gene expression profiles of EP-SCNC patients who achieved clinical benefit revealed enrichment of neuroendocrine differentiation (normalized enrichment score and p-value of a gene set enrichment analysis: 2.1 and 2.1 x 10 -4 ). Principal component analysis showed convergent gene expression profiles of both SCLC and EP-SCNC patients who achieved PR. Pre-treatment tumor of a breast small cell cancer patient who achieved durable response revealed amplifications of multiple genes driving replication stress such as KRAS and CCND1. Longitudinal tumor sampling of the patient through treatment course revealed increasing intra-tumor heterogeneity as a potential resistant mechanism. Conclusions: Combination of berzosertib and topotecan is a novel therapeutic paradigm for patients with EP-SCNCs. Both SCLCs and EP-SCNCs responding to this approach show a similar transcriptional phenotype characterized by high replication stress. Clinical trial information: NCT02487095.
Prognostic factors, and survival difference in gastrointestinal extrapulmonary small cell carcinoma using SEER database.
Authors: Mark Bilinyi Ulanja, Olatunji B. Alese
Journal: Journal of Clinical Oncology (2022)

e16170 Background: Gastrointestinal extrapulmonary small cell carcinoma (GI EPSCCa) is a rare and aggressive tumor. Current treatment guidelines are extrapolated from small cell lung cancer. Factors affecting survival, and the role of primary tumor location are currently unknown. Methods: Using the SEER database to identify patients diagnosed from 2000 to 2018, we used Cox proportional hazard models to assess prognostic factors based on primary tumor location. Results: Of the 1,687 patients included in the analysis, 79.7% were White and 56.9% male. Distribution of the primary location were 31.5% colorectal (CRC), 22.1% Esophagus, 20.6% pancreas, 13.3% hepatobiliary (HB), 10.6% stomach, and 1.8% small intestine (SI). Patients ≥65 years were more likely to have esophago-gastric, SI, HB and pancreatic EPSCCa (P&lt;0.001). Males were more likely to have esophago-gastric, CRC and pancreatic EPSCCa (P&lt;0.001). While Blacks were more likely to have esophago-gastric and SI EPSCCa, Whites were more likely to have CRC, HB and pancreas EPSCCa (P=0.012). There were no racial differences in overall survival (OS) for GI EPSCCa. Male gender (adjusted Hazard Ratio(aHR)=1.12, 95%CI:1.00-1.24, P=0.042), and age ≥65 (aHR)=1.21, 95%CI:1.09-1.35, P=0.001) were associated with inferior OS. Advanced stage at presentation, or not receiving radiation therapy/ chemotherapy were also associated with worse OS. Surgical intervention, and treatment period after 2006 were associated with superior OS (Table) Regarding GI site, HB EPSCCa was associated with inferior OS compared with esophageal EPSCCa (aHR)=1.21, 95%CI:1.00-1.46, P=0.048). SI EPSCCa had a trend toward improved OS (compared to esophageal EPSCCa) (P= 0.237). Conclusions: Chemotherapy, surgery, radiation therapy, female gender, younger age were associated with superior OS for GI EPSCCa, while advanced stage, HB sites (compared to esophageal EPSCCa) were associated with poorer outcome. OS for GI EPSCCa has improved over time. Prospective studies are needed to guide therapy for this aggressive tumor. [Table: see text]
PHACT: Phylogeny-Aware Computing of Tolerance for Missense Mutations
Authors: Nurdan Kuru, Onur Dereli, Emrah Akkoyun, Aylin Bircan, Oznur Tastan, Ogun Adebali
Journal: Molecular Biology and Evolution (2022)

Abstract Evolutionary conservation is a fundamental resource for predicting the substitutability of amino acids and the loss of function in proteins. The use of multiple sequence alignment alone—without considering the evolutionary relationships among sequences—results in the redundant counting of evolutionarily related alteration events, as if they were independent. Here, we propose a new method, PHACT, that predicts the pathogenicity of missense mutations directly from the phylogenetic tree of proteins. PHACT travels through the nodes of the phylogenetic tree and evaluates the deleteriousness of a substitution based on the probability differences of ancestral amino acids between neighboring nodes in the tree. Moreover, PHACT assigns weights to each node in the tree based on their distance to the query organism. For each potential amino acid substitution, the algorithm generates a score that is used to calculate the effect of substitution on protein function. To analyze the predictive performance of PHACT, we performed various experiments over the subsets of two datasets that include 3,023 proteins and 61,662 variants in total. The experiments demonstrated that our method outperformed the widely used pathogenicity prediction tools (i.e., SIFT and PolyPhen-2) and achieved a better predictive performance than other conventional statistical approaches presented in dbNSFP. The PHACT source code is available at https://github.com/CompGenomeLab/PHACT.
Association Between COVID-19 Booster Vaccination and Omicron Infection in a Highly Vaccinated Cohort of Players and Staff in the National Basketball Association
Authors: Caroline G. Tai, Lisa L. Maragakis, Sarah Connolly, John DiFiori, Deverick J. Anderson, Yonatan H. Grad, Christina DeFilippo Mack
Journal: JAMA (2022)

Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by Omicron and Delta Variants